Английская Википедия:Hyper-IL-6
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Hyper-IL-6 is a designer cytokine, which was generated by the German biochemist Stefan Rose-John.[1] Hyper-IL-6 is a fusion protein of the four-helical cytokine Interleukin-6 and the soluble Interleukin-6 receptor which are covalently linked by a flexible peptide linker.[1] Interleukin-6 on target cells binds to a membrane bound Interleukin-6 receptor.[2] The complex of Interleukin-6 and the Interleukin-6 receptor associate with a second receptor protein called gp130, which dimerises and initiates intracellular signal transduction.[3] Gp130 is expressed on all cells of the human body whereas the Interleukin-6 receptor is only found on few cells such as hepatocytes and some leukocytes.[4] Neither Interleukin-6 nor the Interleukin-6 receptor have a measurable affinity for gp130.[5] Therefore, cells, which only express gp130 but no Interleukin-6 receptor are not responsive to Interleukin-6.[5] It was found, however, that the membrane-bound Interleukin-6 receptor can be cleaved from the cell membrane generating a soluble Interleukin-6 receptor.[6] The soluble Interleukin-6 receptor can bind the ligand Interleukin-6 with similar affinity as the membrane-bound Interleukin-6 receptor and the complex of Interleukin-6 and the soluble Interleukin-6 receptor can bind to gp130 on cells, which only express gp130 but no Interleukin-6 receptor.[7] The mode of signaling via the soluble Interleukin-6 receptor has been named Interleukin-6 trans-signaling whereas Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is referred to as Interleukin-6 classic signaling.[8] Therefore, the generation of the soluble Interleukin-6 receptor enables cells to respond to Interleukin-6, which in the absence of soluble Interleukin-6 receptor would be completely unresponsive to the cytokine.[8]
Molecular construction of Hyper-IL-6
In order to generate a molecular tool to discriminate between Interleukin-6 classic signaling and Interleukin-6 trans-signaling, a cDNA coding for human Interleukin-6 and a cDNA coding for the human soluble Interleukin-6 receptor were connected by a cDNA coding for a 13 amino acids long linker, which was long enough to bridge the 40 Å distance between the COOH terminus of the soluble Interleukin-6 receptor and the NH2 terminus of human Interleukin-6.[9] The generated cDNA was expressed in yeast cells and in mammalian cells and it was shown that.[10]
Use of Hyper-IL-6 to analyse IL-6 signaling
Hyper-IL-6 has been used to test which cells depend on Interleukin-6 trans-signaling in their response to the cytokine Interleukin-6. To this end, cells were treated with Interleukin-6 and alternatively with Hyper-IL-6. Cells, which respond to Interleukin-6 alone do express an Interleukin-6 receptor whereas cells, which only respond to Hyper-IL-6 but not to Interleukin-6 alone depend in their response to the cytokine on Interleukin-6 trans-signaling.[11] It turned out that hematopoietic stem cells,[12] neural cells,[13] smooth muscle cells[14] and endothelial cells[15] are typical target cells of Interleukin-6 trans-signaling.
The concept of Interleukin-6 trans-signaling
The Hyper-IL-6 protein has also been used to explore the physiologic role of Interleukin-6 trans-signaling in vivo. It turned out that this signaling mode was involved in many types of inflammation[16] and cancer.[17]
Hyper-IL-6 has helped to establish the concept of Interleukin-6 trans-signaling.[18] Interleukin-6 trans-signaling mediates the pro-inflammatory activities of Interleukin-6 whereas Interleukin-6 classic signaling governs the protective and regenerative Interleukin-6 activities.[19] Recently, in breast cancer patients, it was shown with the help of Hyper-IL-6 that IL-6 trans-signaling via phosphoinositid-3-kinase signaling activates disseminated cancer cells long before metastases are formed.[20] In addition, it was demonstrated in mice that Hyper-IL-6 transneuronal delivery enabled functional recovery after severe spinal cord injury.[21]
References
- ↑ 1,0 1,1 Шаблон:Cite journal
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- ↑ 5,0 5,1 Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ 8,0 8,1 Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Werner-Klein M, Grujovic A, Irlbeck C, Obradović M, Hoffmann M, Koerkel-Qu H, Lu X, Treitschke S, Köstler C, Botteron C, Weidele K, Werno C, Polzer B, Kirsch S, Gužvić M, Warfsmann J, Honarnejad K, Czyz Z, Feliciello G, Blochberger I, Grunewald S, Schneider E, Haunschild G, Patwary N, Guetter S, Huber S, Rack B, Harbeck N, Buchholz S, Rümmele P, Heine N, Rose-John S, Klein CA (2020) Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency. Nat Commun 11(1):4977
- ↑ Leibinger M, Zeitler C, Gobrecht P, Anastasia Andreadaki A, Gisselmann G, Fischer D (2021) Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice. Nat Commun 12(1):391
